title: The lignan (-)-hinokinin displays modulatory effects on human monoamine and GABA transporter activities.
abstract: The neurotransmitter transporters of the SLC6 family play critical roles in the regulation of neurotransmission and are the primary targets of therapeutic agents used to treat clinical disorders involving compromised neurotransmitter signaling. The dopamine and norepinephrine transporters have been implicated in clinical disorders such as attention deficit hyperactivity disorder (ADHD) and substance abuse. The GABA transporters (GATs) serve as a target for anxiolytic, antidepressant, and antiepileptic therapies. In this work, the interaction with neurotransmitter transporters was characterized for a derivative of the lignan (-)-cubebin (1), namely, (-)-hinokinin (2). Using in vitro pharmacological assays, 2 selectively inhibited the human dopamine and norepinephrine transporters, in a noncompetitive manner possibly mediated by binding to a novel site within the transporters, and displayed low affinity for the serotonin transporter. Compound 2 also specifically inhibited the GAT-1 GABA transporter subtype. Compound 2 is not a substrate of the carriers as it had no effect on the efflux of either of the neurotransmitters investigated. This compound is inactive toward glutamate and glycine transporters. These results suggest that 2 may serve as a tool to develop new therapeutic drugs for ADHD and anxiety that target the DAT, NET, and GAT-1 transporters.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Julie Marie V
authors.initials: JM
authors.lastname: Timple
authors.forename: Lizandra Guidi
authors.initials: LG
authors.lastname: Magalhães
authors.forename: Karen Cristina
authors.initials: KC
authors.lastname: Souza Rezende
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Pereira
authors.forename: Wilson Roberto
authors.initials: WR
authors.lastname: Cunha
authors.forename: Márcio Luis
authors.initials: ML
authors.lastname: Andrade e Silva
authors.forename: Ole Valente
authors.initials: OV
authors.lastname: Mortensen
authors.forename: Andréia C K
authors.initials: AC
authors.lastname: Fontana
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D052117:Benzodioxoles; D004149:Dioxoles / Q000737:chemistry / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050485:GABA Plasma Membrane Transport Proteins / Q000502:physiology*; D006801:Humans; D017705:Lignans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D052117:Benzodioxoles; D004149:Dioxoles; D050485:GABA Plasma Membrane Transport Proteins; D017705:Lignans; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C475934:hinokinin; C433065:cubebin; D015107:4-Butyrolactone; D004298:Dopamine; D009638:Norepinephrine